Viral, fungal, protozoal and helminthic infections SYNOPSIS • Viruses present a more difficult problem of chemotherapy than do higher organisms, e.g. bacteria, for they are intracellular parasites that use the metabolism of host cells. Highly selective toxicity is, therefore, harder to achieve. Identification of differences between viral and human metabolism has led to the development of effective antiviral agents, whose roles are increasingly well defined. • Fungus infections range from inconvenient skin conditions to life- threatening systemic diseases; the latter have become more frequent as opportunistic infections in patients immunocompromised by drugs or AIDS, or receiving intensive medical and surgical interventions in ICUs. • Protozoal infections. Malaria is the major transmissible parasitic disease in the world. The life cycle of the plasmodium that is relevant to prophylaxis and therapy is described. Drug resistance is an increasing problem and differs with geographical location, and species of plasmodium. • Helminthic infestations cause considerable morbidity.The drugs that are effective against these organisms are summarised. Viral infections Antiviral agents are most active when viruses are replicating. The earlier that treatment is given, therefore, the better the result. An important difficulty is that a substantial amount of viral multiplication has often taken place before symptoms occur. Apart from primary infection, viral illness is often the consequence of reactivation of latent virus in the body. In both cases patients whose immune systems are compromised may suffer particularly severe illness. Viruses are capable of developing resistance to antimicrobial drugs, with similar implications for the individual patient, for the community and for drug development. An overview of drugs that have proved effective against virus diseases appears in Table 14.1. Herpes simplex and varicella-zoster ACICLOVIR Aciclovir inhibits viral DNA synthesis only after phosphorylation by virus-specific thymidine kinase, which accounts for its high therapeutic index. 257 14 VIRAL, FUNGAL, PROTOZOAL AND HELMINTHIC INFECTIONS TABLE 1 4. 1 Drugs of choice for virus infections Organism Varicella-zoster chickenpox zoster Herpes simplex keratitis labial genital encephalitis disseminated Human immunodeficiency virus (HIV) Hepatitis B, C or D Influenza A Cytomegalovirus (CMV) Respiratory syncytial virus Drug of choice aciclovir aciclovir or famciclovir aciclovir(topical) aciclovir (topical and/or oral) aciclovir (topical and/or oral) famciclovir (oral) aciclovir aciclovir zidovudine didanosine ritonavir indinavir saquinavir nelfmavir interferon alfa-2a and 2b zanamivir ganciclovir tribavirin Alternative valaciclovir or famciclovir valaciclovir valaciclovir valaciclovir penciclovir foscarnet zalcitabine stavudine lamivudine nevirapine abacavir efavirenz lamivudine amantadine foscarnet (for retinitis in HIV patients) oidofovir Phosphorylated aciclovir inhibits DNA polymerase and so prevents viral DNA being formed. It eff- ectively treats susceptible herpes viruses if started early in the course of infection, but it does not eradicate persistent infection. Taken orally about 20% is absorbed from the gut, but this is sufficient for the systemic treatment of some infections. It distributes widely in the body; the concentration in CSF is approximately half that of plasma, and the brain concentration may be even less. These differences are taken into account in dosing for viral encephalitis (for which aciclovir must be given i.v). The drug is excreted in the urine (t l / 2 3 h). For oral and topical use the drug is given x 5/d. Indications for aciclovir include: Herpes simplex virus: • skin infections, including initial and recurrent labial and genital herpes (as a cream), most effectively when new lesions are forming; skin and mucous membrane infections (as tablets or oral suspension) • ocular keratitis (as an ointment) • prophylaxis and treatment in the immunocompromised (oral, as tablets or suspension) • encephalitis, disseminated disease (i.v.). Aciclovir-resistant herpes simplex virus has been reported in patients with AIDS; foscarnet (see p. 262) has been used in these cases. Varicella-zoster virus: • chickenpox, particularly in the immunocompromised (i.v.) or in the immunocompetent with pneumonitis or hepatitis (i.v.) • shingles in immunocompetent persons (as tablets or suspension, and best within 48 h of the appearance of the rash). Immunocompromised persons will often have more severe symptoms and require i.v. administration. Adverse reactions are remarkably few. The oph- thalmic ointment causes a mild transient stinging sensation and a diffuse superficial punctate ker- atopathy which clears when the drug is stopped. Oral or i.v. use may cause gastrointestinal symp- toms, headache and neuropsychiatric reactions. Extravasation with i.v. use causes severe local inflammation. Valaciclovir is a prodrug (ester) of aciclovir, i.e. after oral administration the parent aciclovir is released. The higher bioavailability of valaciclovir (about 60%) allows dosing only 8-hourly. It is used for treating herpes zoster infections and herpes simplex infections of the skin and mucous membranes. Famciclovir is a prodrug of penciclovir which is similar to aciclovir; it is used for herpes zoster and genital herpes simplex infections. It need be given only 8-hourly. Penciclovir is also available as a cream for treatment of labial herpes simplex. Idoxuridine was the first widely used antivirus drug. It is superseded by aciclovir and is variably effective topically for ocular and cutaneous herpes simplex with few adverse reactions. 258 14 HUMAN IMMUNODEFICIENCY VIRUS (HIV) Human immunodeficiency virus (HIV) GENERAL PRINCIPLES • No current antiviral agents or combinations eliminate HIV infection, but the most effective combinations (so-called highly-active anti- retroviral therapy, HAART) produce profound suppression of viral replication in many patients which results in useful reconstitution of the immune system. This can be measured by a fall in the plasma viral load and an increase in the numbers of cytotoxic T-cells (CD4 count) in patients' plasma. Rates of opportunistic infections such as Pneumocystis carinii pneumonia and CMV retinitis are reduced in patients with restored CD4 counts and their life-expectancy is markedly increased. Efficacy of viral suppression, however, must be balanced against the risks of unwanted effects from the multiple drugs used. Combination therapy reduces the risks of emergence of resistance to antiretroviral drugs, which is increasing in incidence even in patients newly-diagnosed with HIV. • HAART comprises two nucleoside reverse transcriptase inhibitors used with either a non- nucleoside reverse transcriptase inhibitor or one or two protease inhibitors. • The decision to begin antiretroviral therapy is based on the CD4 cell count, the plasma viral load and the intensity of the patient's clinical symptoms. Therapy is switched to alternative combinations if these variables deteriorate. Available information about drugs and combinations is accumulating monthly and the choice of agents is best made after reference to contemporary, expert advice. • Pregnancy and breast-feeding pose especial problems; therapy at this time is aimed to minimise toxicity to the fetus while reducing maternal viral load and the catastrophic results of HIV transmission to the neonate. Prevention of maternal-fetal and maternal-infant transmission is the most cost-effective way of using antiretroviral drugs in less developed countries. • Combination antiretroviral therapy is associated with redistribution of body fat in some patients ('lipodystrophy syndrome'), and protease inhibitors may disturb lipid and glucose metabolism. Appropriate laboratory tests to monitor these effects should be performed. • Impaired cell-mediated immunity leaves the host prey to many (opportunistic) infections including: candidiasis, coccidioidomycosis, cryptosporidiosis, cytomegalovirus disease, herpes simplex, histoplasmosis, Pneumocystis carinii pneumonia, toxoplasmosis and tuberculosis (with multiply-resistant organisms). Treatment of these conditions is referred to elsewhere in this text; for a comprehensive review of the antimicrobial prophylaxis of opportunistic infections in patients with HIV infection, readers are referred to Kovacs & Masur 2000 New England Journal of Medicine 342:1416. Antiretroviral drugs may also be used in com- bination to reduce the risks of acquisition of HIV from accidental needlestick injuries from HIV- contaminated sharps such as needles. The decision to offer this postexposure prophylaxis (PEP), and the optimal combination of drugs used, should be made by experts and administration must begin rapidly (within a few hours of the injury). NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Zidovudine (Retrovir) The human immunodeficiency virus replicates by converting its single-standed RNA into double- stranded DNA which is incorporated into host DNA; this crucial conversion, the reverse of the normal cellular transcription of nucleic acids, is accomplished by the enzyme reverse transcriptase. Zidovudine, as the triphosphate, was the first anti- HP/ drug to be introduced and has a high affinity for reverse transcriptase. It is integrated by it into the viral DNA chain, causing premature chain ter- mination. The drug must be present continuously to prevent viral alteration of the host DNA, which is permanent once it occurs. 259 14 VIRAL, FUNGAL, PROTOZOAL AND HELMINTHIC INFECTIONS Pharmacokinetics. Zidovudine is well absorbed from the gastrointestinal tract (it is available as capsules and syrup) and is rapidly cleared from the plasma (t l / 2 1 h); concentrations in CSF are approx- imately half those in plasma. It is also available i.v. for patients temporarily unable to take oral med- ications. The drug is mainly metabolically inacti- vated, but 20% is excreted unchanged by the kidney. Uses. Zidovudine is indicated for serious manifes- tations of HIV infection in patients with acquired immunodeficiency syndrome (AIDS) or AIDS- related complex, i.e. those with opportunistic infec- tion, constitutional or neurological symptoms, or with low CD4 counts; treatment reduces the frequency of opportunistic infections and prolongs survival when used in effective combinations. It is also indicated alone for pregnant women and their offspring for prevention of maternal-fetal HIV transmission. Adverse reactions early in treatment may include anorexia, nausea, vomiting, headache, dizziness, malaise and myalgia, but tolerance develops to these and usually the dose need not be altered. More serious are anaemia and neutropenia which develop more commonly when the dose is high, and with advanced disease. A toxic myopathy (not easily distinguishable from HlV-associated myopathy) may develop with long-term use. Rarely, a syndrome of hepatic necrosis with lactic acidosis may occur with zidovudine (and with other reverse transcriptase inhibitors). Didanosine (DDI) has a much longer intracellular duration than zidovudine and thus prolonged antiretroviral activity. Didanosine is rapidly but incompletely absorbed from the gastrointestinal tract and is widely distributed in body water; 30-65% is recovered unchanged in the urine which it enters both by glomerular filtration and tubular secretion (t l / 2 1h). Didanosine may cause pancreatitis with an incidence of 7% at a dose of 500 mg/d; a reduced dose may be tolerated after symptoms have resolved. Other adverse effects include peripheral neuropathy, hyperuricaemia and diarrhoea, any of which may give reason to reduce the dose or discontinue the drug. It reduces gastric acidity, which impairs absorption of a number of drugs frequently used in patients with AIDS including dapsone, ketoconazole, quinolones and indinavir. Zalcitabine (DDC) (t 1 / 2 1h) is similar. Adverse effects include peripheral neuropathy, hepatitis and pancreatitis which are reason to discontinue the drug. Oral ulceration, gastrointestinal symptoms and bone marrow suppression have also been reported. Lamivudine (3TC) is a reverse transcriptase inhibitor with a relatively long intracellular half-life (14 h; plasma t 1 / 2 6 h). In combination with zidovudine, lamivudine appears to reduce viral load effectively and to be well tolerated, although bone marrow suppression may be produced. Rarely, pancreatitis may occur. Lamivudine has also been used for treatment of chronic hepatitis B infection, but res- istant strains of virus have been reported. Abacavir (t 1 / 2 2 h) may be the most potent reverse transcriptase inhibitor. It is usually well-tolerated, but adverse effects may include hypersensitivity reactions especially during the first 6 weeks of therapy. Stavudine (t 1 / 2 1 h). Hepatic toxicity and pancreatitis have been reported, and a dose-related peripheral neuropathy may occur. PROTEASE INHIBITORS Protease inhibitors constitute a new class of agent for HIV infection. In its process of replication, HIV produces protein and also a protease which cleaves the protein into component parts that are sub- sequently reassembled into virus particles; protease inhibitors disrupt this essential process. Protease inhibitors have been shown to reduce viral RNA concentration (Viral load'), increase the CD4 count and improve survival when used in combination with other agents and compared against placebo. They are extensively metabolised by isoenzymes of the cytochrome P450 system, notably by CYP 3A4 which is involved in the metabolism of many drugs. Plasma t l / 2 for each of these is in the range 2-4 h. The drugs have broadly similar therapeutic effects and include: 260 14 Amprenavir, indinavir, lopinavir, nelfmavir, ritonavir and saquinavir Adverse effects. A variety of effects has been asso- ciated with these agents, including gastrointestinal disturbance, headache, dizziness, sleep disturbance, raised liver enzymes, neutropenia, pancreatitis, and rashes. INFLUENZA A Anti-HIV drugs are the subject of intense research and development and several new agents belonging to one or other of the above classes are to be expected. InfluenzaA Interactions. Involvement of protease inhibitors with the cytochrome P450 system provides scope for interaction with numerous substances. Agents that induce P450 enzymes (e.g. rifampicin, St John's wort) accelerate their metabolism, and reduce plasma concentration; enzyme inhibitors (e.g. ketoconazole, cimetidine) raise their plasma concentration; competition with other drugs for the cytochrome enzymes can lead to variable results. Ritonavir is itself a powerful inhibitor of CYP 3A4 and CYP 2D6. This effect is utilised when ritonavir in small quantity is combined (in capsules) with lopinavir to inhibit its metabolism and increase its therapeutic efficacy. The present account should be sufficient to warn the physician, and thereby the patient, to take particular heed when seeking to co-administer any drug a with protease inhibitor. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Efavirenz has a long duration of action and need be taken only once per day (t l / 2 52 h). Rash is relatively common during the first 2 weeks of therapy, but resolution usually occurs within a further 2 weeks; the drug should be stopped if the rash is severe or if there is blistering, desquamation, mucosal involvement or fever. Neurological adverse reactions occur and may be reduced by taking the drug; gastrointestinal side effects, hepatitis and pancreatitis have also been reported. Nevirapine is used in combination with at least two other antiretroviral drugs, usually for progressive or advanced HIV infection, although it appears effective also in pregnancy. It penetrates the CSF well, and undergoes hepatic metabolism (t 1 / 2 , 28 h). It is taken once daily, increasing to twice daily if rash is not seen. Rash and hepatitis are the commonest side effects. Amantadine Amantadine is effective only against influenza A; it acts by interfering with the uncoating and release of viral genome into the host cell. It is well absorbed from the gastrointestinal tract and is eliminated in the urine (t 1 / 2 3 h). Amantadine may be used orally for the prevention and treatment of infection with influenza A (but not influenza B) virus. Those most likely to benefit include the debilitated, persons with respiratory disability and people living in crowded conditions, especially during an influenza epidemic. Adverse reactions include dizziness, nervousness, lightheadedness and insomnia. Drowsiness, hal- lucinations, delirium and coma may occur in patients with impaired renal function. Convulsions may be induced, and amantadine should be avoided in epileptic patients. Amantadine for Parkinson's disease: see page 404. Zanamivir (Relenza) Zanamivir is a neuraminidase inhibitor which blocks entry of the influenza A and B viruses to target cells and the release of their progeny. It is administered as 5 mg of a dry powder twice daily in 5-day course via a special inhaler. Controlled trials have shown that the duration of symptoms is reduced from about 6 to 5 days, with a smaller reduction in the mean time taken to return to normal activities. In high-risk groups the reduction in duration of symptoms is a little greater, and fewer patients need antibiotics. Zanamivir was one of the first medicines to be the subject of a technology appraisal by the National Institute for Clinical Excellence (NICE) in the UK. NICE recommends that it be reserved for: at-risk patients (those with chronic respiratory or cardio- vascular disease, immunosuppression or diabetes mellitus, or over the age of 65); when virological 261 14 VIRAL, FUNGAL, PROTOZOAL AND HELMINTHIC INFECTIONS surveillance in the community indicates that influen- za virus is circulating; and only for those who present within 48 h of the onset of influenza-like symptoms. Unwanted effects are uncommon, but bronchospasm may be precipitated in asthmatics and gastro- intestinal disturbance and rash are occasionally seen. Cytomegalovirus when other drugs are unsuitable. Nephrotoxicity is common, but is reduced by hydration with i.v. fluids before each dose and co-administration with probenecid. A variety of other side effects has been reported, including bone marrow suppression, nausea and vomiting, and iritis and uveitis. Respiratory syncytial virus (RSV) Ganciclovir Ganciclovir is similar to aciclovir in its mode of action, but is much more toxic. It is given i.v. or orally and is eliminated in the urine, mainly unchanged (t l / 2 4 h). Ganciclovir is active against several types of virus but because of toxicity, its i.v. use is limited to life- or sight-threatening cytomegalo- virus (CMV) infection in immunocompromised patients, and (by mouth) for maintenance suppres- sive treatment of retinitis in patients with AIDS, and to prevent CMV disease in patients receiving immunosuppressive therapy following organ trans- plantation (especially liver transplants). Ganciclovir- resistant cytomegalovirus isolates have been reported. Adverse reactions include neutropenia and throm- bocytopenia which are usually but not always reversible after withdrawal. Concomitant use of potential marrow-depressant drugs, e.g. cotrimox- azole, amphotericin B, zidovudine, should be avoided. Other reactions are fever, rash, gastro- intestinal symptoms, confusion and seizure (the last especially if imipenem is coadministered). Foscarnet is used i.v. for retinitis due to CMV in patients with HIV infection when ganciclovir is contraindicated; it has also been used to treat aciclovir-resistant herpes simplex virus infection (see p. 258). It causes numerous adverse effects, including renal toxicity, nausea and vomiting, neurological reactions and marrow suppression. Cidofovir is given by i.v. infusion (usually every 1-2 weeks) for CMV retinitis in patients with AIDS Ribavirin (Tribavirin) is a synthetic nucleoside which may be administered by inhalation via a special ventilator for RSV bronchiolitis in infants and children. Efficacy for this indication is controversial, and it is usually reserved for the most severe cases, and those with co-existing illnesses, such as immunosuppression. Systemic absorption by the inhalational route is negligible. It is effective by mouth (t 1 / 2 45 h) in treating Lassa fever and, when combined with interferon alfa-2b, for chronic hepatitis C infection (see below). Systemic ribavirin is an important teratogen, and it may cause cardiac, haematological, gastrointestinal and neurological side effects. Palivizumab may be given by monthly i.m. injec- tion in the winter and early spring to infants at high risk of suffering RSV infection. Transient fever and local injection site reactions are seen, and rarely gastrointestinal disturbance, rash, leucopenia or disturbed liver function may occur. Drugs that modulate the host immune system Interferons Virus infection stimulates the production of pro- tective glycoproteins (interferons) which act: (1) directly on uninfected cells to induce enzymes that degrade viral RNA; (2) indirectly by stimulating the immune system. Interferons will also modify cell regulatory mechanisms and inhibit neoplastic 262 14 SUPERFICIAL MYCOSES growth. They are classified as alfa, beta or gamma according to their antigenic and physical properties. Alfa interferons (subclassified -2a, -2b and -Nl) are effective against conditions that include hairy cell leukaemia, chronic myelogenous leukaemia, recur- rent or metastatic renal cell carcinoma, Kaposi's sarcoma in AIDS patients (an effect that may be partly due to its activity against HIV) and condylomata acuminata (genital warts). Interferon alfa-2a and -2b also improve the man- ifestations of viral hepatitis, but responses differ according to the infecting agent (see p. 658). Whereas patients with hepatitis B and C may respond to interferon alfa, those with hepatitis C have a higher rate of relapse and may need prolonged therapy. Interferon alfa-2b has been used in combination with ribavirin for moderate to severe, chronic hepatitis C infection, but not in patients who are heavy imbibers of alcohol because of the risks of liver damage. Successful treatment results in the serum concentra- tion of viral RNA becoming undetectable by poly- merase chain reaction (PCR). Hepatitis D requires a much larger dose of interferon to obtain a response and yet relapse may occur if the drug is withdrawn. Adverse reactions are common and include an influenza-like syndrome (naturally-produced inter- feron may cause symptoms in natural influenza infection), fatigue and depression which respond to lowering the dose. Other effects are anorexia (suf- ficient to induce weight loss), convulsions, hypo- tension, hypertension, cardiac arrhythmias and bone marrow depression. Interferons inhibit the metabolism of theophylline, increasing its effect. Inosine pranobex This drug is reported to stimulate the host immune response to virus infection and has been used for mucocutaneous herpes simplex and genital warts (but aciclovir is superior). It is administered by mouth and metabolised to uric acid, so should be used with caution in patients with hyperuricaemia or gout. Fungal infections Widespread use of immunosuppressive chemo- therapy and the emergence of AIDS have contributed to a rise in the incidence of opportunistic infection ranging from comparatively trivial cutaneous infec- tions to systemic disease that demands prolonged treatment with potentially toxic agents. In hospital, Candida infections have risen over 10-fold over the past decade, and associated usage of antifungal drugs has risen markedly. Superficial mycoses DERMATOPHYTE INFECTIONS (ringworm, tinea) Longstanding remedies such as Compound Benzoic Acid Ointment (Whitfield's ointment) are still acceptable for mild infections but a topical imidazole (clotrimazole, econazole, miconazole, sulconazole), which is also effective against Candida, is now usually preferred. Tioconazole is effective topically for nail infections. If multiple areas are affected, especially if the scalp or nails are included, and if topical therapy fails, oral itraconazole or terbinafine are used. Griseofulvin has largely been superseded for these indications. CANDIDA INFECTIONS Cutaneous infection is generally treated with topical amphotericin, clotrimazole, econazole, miconazole or nystatin. Local hygiene is also important. An under- lying explanation should be sought if a patient fails to respond to these measures, e.g. diabetes, the use of a broad-spectrum antibiotic or of immunosuppressive drugs. Candidiasis of the alimentary tract mucosa responds to amphotericin, fluconazole, ketoconazole, miconazole or nystatin as lozenges (to suck, for oral infection), gel (held in the mouth before swallowing), suspension or tablets. Vaginal candidiasis is treated by clotrimazole, econazole, isoconazole, ketoconazole, miconazole or nystatin as pessaries or vaginal tablets or cream inserted once or twice a day with cream or ointment on surrounding skin. Failure may be due to a concurrent intestinal infection causing reinfection and nystatin tablets may be given by mouth 263 14 VIRAL, FUNGAL, PROTOZOAL AND HELMINTHIC INFECTIONS 8-hourly with the local treatment. Alternatively, oral fluconazole therapy may be used, and this is now available without prescription ('over the counter' medication) in the UK. The male sexual partner may use a similar antifungal ointment for his benefit and for hers (reinfection). Fluconazole is often given orally or i.v. to heavily immunocompromised patients (e.g. during periods of profound granulocytopenia) and to severely ill patients on intensive care units to reduce the incidence of systemic candidiasis. Systemic mycoses The principal treatment options are summarised in Table 14.2. Pneumocystosis, caused by Pneumocystis carinii (now classified as a fungus), is an important cause of potentially fatal pneumonia in the irnmuno- suppressed. It is treated with co-trimoxazole in high dose (120 mg/kg daily in 2-4 divided doses for 14 days by mouth or i.v. infusion). Intolerant or resistant cases may benefit from pentamidine or, if mild to moderate, from atovaquone, or trimetrexate (given with calcium folinate). Co-trimoxazole by mouth or intermittent inhaled pentamidine are used for prophylaxis in patients with AIDS. Drugs that disrupt the fungal cell membrane potyenes: e.g. amphotericin azotes: imidazoles, e.g. ketoconazole triazoles, e.g. fluconazole allylamine: terbinafine Drug that inhibits mitosis: griseofulvin Drug that inhibits DMA synthesis: flucytosine TABLE 14.2 Drugs of choice for some fungal infections Infection Aspergillosis Blastomycosis ' Candidiasis mucosal systemic Coccidiodoidomycosis ' Cryptococcosis chronic suppression Histoplasmosis chronic suppression 3 Mucormycosis Paracoccidioidomycosis Pseudallescheriasis Sporotrichosis cutaneous deep Drug of first choice amphotericin itraconazole or amphotericin fluconazole or amphotericin amphotericin or flucytosine fluconazole or amphotericin amphotericin + flucytosine fluconazole or itraconazole itraconazole or amphotericin itraconazole amphotericin itraconazole or amphotericin ketoconazole or itraconazole itraconazole amphotericin Alternative itraconazole ketoconazole 2 or fluconazole itraconazole or ketoconazole or fluconazole itraconazole or ketoconazole 2 or fluconazole fluconazole or itraconazole amphotericin (weekly) ketoconazole 2 amphotericin no dependable alternative ketoconazole 2 potassium iodide Itraconazole or fluconazole Drugs that disrupt the fungal cell membrane 1 Patients with severe illness, meningitis.AIDS or some other causes of immunosuppression should receive amphotericin. 2 Continue treatment for 6-12 months. 3 For patients with AIDS. This Table is drawn substantially from the Medical Letter on Drugs and Therapeutics (200l,USA).We are grateful to the Chairman of the Editorial Board for permission to publish the material (PNB, MIB). membranes. The resulting deformity of the mem- brane allows leakage of intracellular ions and enzymes, causing cell death. Those polyenes that have useful antifungal activity bind selectively to ergosterol, the most important sterol in fungal (but not mammalian) cell walls. POLYENE ANTIBIOTICS These act by binding tightly to sterols present in cell Amphotericin (amphotericin B) Amphotericin is negligibly absorbed from the gut 264 14 DRUGSTHAT DISRUPTTHE FUNGAL CELL MEMBRANE and must be given by i.v. infusion for systemic infection; about 10% remains in the blood and the fate of the remainder is not known but it is probably bound to tissues. The t l / 2 is 15 d, i.e. after stopping treatment, drug persists in the body for several weeks. Amphotericin is at present the drug of choice for most systemic fungal infections (see Table 14.2). The diagnosis of systemic infection should whenever possible be firmly established because toxicity from conventional amphotericin is significant and the lipid-associated formulations are very expensive; tissue biopsy and culture may be necessary. New molecular diagnostic methods based on the polymerase chain reaction to detect aspergillus DNA may soon revolutionise management of invasive infection. A conventional course of treatment for filamentous fungal infection lasts 6-12 weeks during which at least 2 g of amphotericin is given (usually 1 mg/kg/day), but lower total and daily (e.g. 0.6 mg/kg) doses are used for Candida infections with correspondingly lower rates of adverse drug reactions. Lipid-associated formulations of amphotericin offer the prospect of reduced risk of toxicity while retaining therapeutic efficacy. In an aqueous medium, a lipid with hydrophilic and hydrophobic properties will form vesicles (liposomes) comprising an outer lipid bilayer surrounding an aqueous centre. The AmBisome formulation incorporates amphotericin in a lipid bilayer (diameter 55-75 nm) from which the drug is released. Amphotericin is also for- mulated as other lipid-associated complexes, e.g. Abelcet ('amphotericin B lipid complex'), and Amphocil ('amphotericin B colloidal dispersion'). Experience with these formulations is growing; AmBisome is the most established, and it is sig- nificantly less toxic but much more expensive than conventional amphotericin. It may be more effective for some indications, probably because higher doses may safely be given more quickly (e.g. 3 mg/kg/day). It is the first choice for patients with impaired renal function, but treatment is often begun with the conventional formulation in those with normal kidneys. Therapy can be transferred to AmBisome if the patient's renal function deteriorates. Further clinical trials are needed to establish the best clinically and cost effective ways to use these drugs. Adverse reactions. Gradual escalation of the dose limits toxic effects but these may have to be accepted in life-threatening infection if conventional ampho- tericin is used. Renal impairment is invariable, although reduced by adequate hydration and ampho- tericin need not be stopped until serum creatinine has risen to 180-200 micromol/1; the same dose may then be resumed after 3-5 days. Amphotericin nephrotoxicity is reversible, at least in its early stages. Hypokalaemia (due to distal renal tubular acidosis) may necessitate replacement therapy. Other adverse effects include: anorexia, nausea, vomiting, malaise, abdominal, muscle and joint pains, loss of weight, anaemia, hypomagnesaemia and fever. Aspirin, an antihistamine (H l receptor) or an anti- emetic may alleviate symptoms. Severe febrile re- actions are mitigated by hydrocortisone 25-50 mg before each infusion. Lipid-formulated preparations are much less often associated with adverse reactions, but fever, chills, nausea, vomiting, nephrotoxicity, electrolyte disturbance and occasional hepatotoxicity have been reported. Nystatin (named after New York State Health Laboratory) Nystatin is too toxic for systemic use. It is not absorbed from the alimentary canal and is used to prevent or treat superficial candidiasis of the mouth, oesophagus or intestinal tract (as suspension, tablets or pastilles), for vaginal candidiasis (pessaries) and cutaneous infection (cream, ointment or powder). AZOLES The antibacterial, antiprotozoal and anthelminthic members of this group are described in the appro- priate sections. Antifungal azoles comprise the following: • Imidazoles (ketoconazole, miconazole, fenticonazole, clotrimazole, isoconazole, tioconazole) interfere with fungal oxidative enzymes to cause lethal accumulation of hydrogen peroxide; they also reduce the formation of ergosterol, an important constituent of the fungal cell wall which thus becomes permeable to intracellular constituents. Lack of selectivity in these actions results in important adverse effects. • Triazoles (fluconazole, itraconazole) damage the 265 14 VIRAL, FUNGAL, PROTOZOAL AND HELMINTHIC INFECTIONS fungal cell membrane by inhibiting a demethylase enzyme; they have greater selectivity against fungi, better penetration of the CNS, resistance to degradation and cause less endocrine disturbance than do the imidazoles. Ketoconazole Ketoconazole is well absorbed from the gut (poorly where there is gastric hypoacidity, see below); it is widely distributed in tissues but concentrations in CSF and urine are low; its action is terminated by metabolism by cytochrome P450 3A (CYP 3A) (i l / 2 8 h). Ketoconazole is effective by mouth for systemic mycoses (see Table 14.2) but has been superseded by fluconazole and itraconazole for many indications largely on grounds of improved pharmacokinetics, unwanted effect profile and efficacy. Impairment of steroid synthesis by keto- conazole has been put to other uses, e.g. inhibition of testosterone synthesis lessens bone pain in patients with advanced androgen-dependent prostatic cancer. Adverse reactions include nausea, giddiness, head- ache, pruritus and photophobia. Impairment of testosterone synthesis may cause gynaecomastia and decreased libido in men. Of particular concern is impairment of liver function, ranging from transient elevation of hepatic transaminases and alkaline phosphatase to severe injury and death. Interactions. Drugs that lower gastric acidity, e.g. antacids, histamine H 2 receptor antagonists, impair the absorption of ketoconazole from the gastro- intestinal tract. Like all imidazoles, ketoconazole binds strongly to several cytochrome P450 iso- enzymes and thus inhibits the metabolism (and increases effects of) oral anticoagulants, phenytoin and cyclosporin, and increases the risk of cardiac arrhythmias with terfenadine. A disulfiram-like reaction occurs with alcohol. Concurrent use of rifampicin, by enzyme induction of CYP 3A, markedly reduces the plasma concentration of ketoconazole. Miconazole is an alternative. Clotrimazole is an effective topical agent for dermatophyte, yeast, and other fungal infections (intertrigo, athlete's foot, ringworm, pityriasis versicolor, fungal nappy rash). Econazole and sulconazole are similar. Tioconazole is used for fungal nail infections and isoconazole and fenticonazole for vaginal candidiasis. Fluconazole Fluconazole is absorbed from the gastrointestinal tract and is excreted largely unchanged by the kidney (i l / 2 30 h). It is effective by mouth for oropharyngeal and oesophageal candidiasis, and i.v. for systemic candidiasis and cryptococcosis (including crypto- coccal meningitis; it penetrates the CSF well). It is used prophylactically in a variety of conditions predisposing to systemic Candida infections, includ- ing at times of profound neutropenia after bone marrow transplantation, and in patients in Intensive Care Units who have intravenous lines in situ, are receiving antibiotic therapy and have undergone bowel surgery. It may cause gastrointestinal dis- comfort, headaches, elevation of liver enzymes and allergic rash, but is generally very well tolerated. Animal studies demonstrate embryotoxicity and flu- conazole ought not to be given to pregnant women. High doses increase the effects of phenytoin, cyclo- sporin, zidovudine and warfarin. Itraconazole Itraconazole is available for oral and i.v. admin- istration. Absorption from the gut is about 55% and is variable. It is improved by ingestion with food, but decreased by fatty meals and therapies that reduce gastric acidity, and is often reduced in patients with AIDS; to assure adequacy of therapy, serum concen- trations should be assayed during prolonged use for critical indications. It is heavily protein bound and virtually none is found within the CSF. Itraconazole is almost completely oxidised by the liver (it is a substrate for CYP 3A), and excreted in the bile; little unchanged drug enters the urine (t 1 / 2 25 h, increasing to 40 h with continuous treatment). Itraconazole is used for a variety of superficial mycoses, as a prophylactic agent for aspergillosis and candidiasis in the immunocompromised, and i.v. for treatment of histoplasmosis. It is licensed in the UK as a second line agent for Candida, Aspergillus and Cryptococcus infections, and it may be convenient as 'follow on' therapy after systemic aspergillosis has been brought under control by an amphotericin preparation. It 266 14 [...]... transmission of the infection because the patient becomes noninfective and the parasite fails to develop in the mosquito (site 4) In summary, drugs may be selected for: • treatment of clinical attacks • prevention of clinical attacks • radical cure Drugs used for malaria, and their principal actions are classified in Table 14.3 DRUG-RESISTANT MALARIA Drug-resistant parasites constitute a persistent... Erythrocyte cycle (site 2 in Fig 14.1) Merozoites enter red cells where they develop into schizonts which form more merozoites which are released when the cells burst giving rise to the features of the clinical attack The merozoites reenter red cells and the cycle is repeated Chloroquine, quinine, mefloquine, halofantrine, proguanil, pyrimethamine, and tetracyclines (blood schizontocides) kill these... Helminths have complex life-cycles, special knowl276 HELMINTHIC INFECTIONS edge of which is required by those who treat infections Table 14.5 will suffice here Drug resistance has not so far proved to be a clinical problem, though it has occurred in animals on continuous chemoprophylaxis Drugs for helminthic infections Albendazole is similar to mebendazole (below) Diethylcarbamazine kills both microfilariae . patient's renal function deteriorates. Further clinical trials are needed to establish the best clinically and cost effective ways to use . 4). In summary, drugs may be selected for: • treatment of clinical attacks • prevention of clinical attacks • radical cure. Drugs used for malaria,